EP3027588A2 - Novel complexes of agomelatine and sulphonic acids, method for preparing same and the pharmaceutical compositions that contain them - Google Patents

Novel complexes of agomelatine and sulphonic acids, method for preparing same and the pharmaceutical compositions that contain them

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Publication number
EP3027588A2
EP3027588A2 EP14758162.3A EP14758162A EP3027588A2 EP 3027588 A2 EP3027588 A2 EP 3027588A2 EP 14758162 A EP14758162 A EP 14758162A EP 3027588 A2 EP3027588 A2 EP 3027588A2
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EP
European Patent Office
Prior art keywords
agomelatine
disorders
complex
formula
theta
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP14758162.3A
Other languages
German (de)
French (fr)
Other versions
EP3027588B1 (en
Inventor
Hanbin Shan
Yuhui SHEN
Ying Luo
Philippe Letellier
Michael Lynch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Shanghai Institute of Pharmaceutical Industry
Laboratoires Servier SAS
Original Assignee
Shanghai Institute of Pharmaceutical Industry
Laboratoires Servier SAS
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Filing date
Publication date
Priority claimed from PCT/CN2013/080337 external-priority patent/WO2015013865A1/en
Priority claimed from FR1360124A external-priority patent/FR3012142B1/en
Priority to MEP-2020-125A priority Critical patent/ME03741B/en
Application filed by Shanghai Institute of Pharmaceutical Industry, Laboratoires Servier SAS filed Critical Shanghai Institute of Pharmaceutical Industry
Priority to PL14758162T priority patent/PL3027588T3/en
Priority to RS20200720A priority patent/RS60440B1/en
Priority to SI201431601T priority patent/SI3027588T1/en
Publication of EP3027588A2 publication Critical patent/EP3027588A2/en
Publication of EP3027588B1 publication Critical patent/EP3027588B1/en
Application granted granted Critical
Priority to HRP20200927TT priority patent/HRP20200927T1/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/33—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems
    • C07C309/34—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton of six-membered aromatic rings being part of condensed ring systems formed by two rings
    • C07C309/35—Naphthalene sulfonic acids
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    • A61K31/16—Amides, e.g. hydroxamic acids
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/32—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of salts of sulfonic acids
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Definitions

  • the present invention relates to novel complexes of agomelatine and sulfonic acids, their method of preparation as well as pharmaceutical compositions containing them.
  • Agomelatine is marketed under the brand name Valdoxan® or Thymanax® by the French group Servier as an agonist of receptors of the melatoninergic system and antagonist of the 5-HT 2C. It is the first melatoninergic antidepressant, useful in the treatment of major depression, improving sleep and sexual function.
  • the object of the present invention is to elaborate complexes of agomelatine and sulfonic acids having the particular stoichiometry of 2 molar equivalents of agomelatine per 1 molar equivalent of sulfonic acids. These complexes have excellent properties in terms of solubility, stability and purity, making it possible to envisage their use for the manufacture of pharmaceutical compositions containing agomelatine. Moreover, the stoichiometry of the complexes according to the present invention confers a weight advantage in favor of the active ingredient of the complex Le. agomelatine, making it possible to develop pharmaceutical formulations containing smaller amounts of complex.
  • the present invention relates to agomelatine and sulfonic acid complexes having the structure of formula (I):
  • x is 0 or 1
  • SO 3 H is 1,5-naphthalene disulfonic acid or benzene sulfonic acid.
  • the preferred compounds according to the invention are the following complexes of agomelatine and sulphonic acids:
  • the agomelatine / 1,5-naphthalene disulfonic acid (2/1) complex is characterized by its powder X-ray diffraction pattern shown in FIG. 1, measured on a Panalytical Xpert Pro MPD (copper anticathode) diffractometer.
  • the main lines are expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ⁇ 0.2), and relative intensity (expressed as a percentage of the most intense line). are listed in Table 1:
  • Table 1 Table of diffraction peaks of the complex agomelatine / 1,5-naphthalene disulfonic acid (2/1)
  • the complex of the present invention is characterized by the X-ray diffraction measurement
  • there may be errors in the measurement of the identified peaks sometimes attributable to the equipment or conditions used. More particularly, the 2 theta values may have an error of about ⁇ 0.2, and sometimes an error of about ⁇ 0.1 even if high-tech equipment is used.
  • the measurement error must be taken into account when identifying the structure of the complex.
  • the agomelatine / 1,5-naphthalene disulfonic acid complex (2/1) is also characterized by DSC (differential scanning calorimetry) in the spectrum shown in Figure 2, which shows an endotherm corresponding to the fusion of the complex at a temperature of about 237 ° C.
  • the invention also relates to the complex agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate which is characterized by its powder X-ray diffraction pattern shown in Figure 3, measured on a Panalytical Xpert Pro MPD (anticathode) diffractometer. copper).
  • the main lines are expressed as inter-reticular distance d, Bragg angle 2 theta (expressed in ⁇ 0.2), and relative intensity (expressed as a percentage of the most intense line). are listed in Table 2:
  • Table 2 Table of diffraction peaks of the complex agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate
  • the complex of the present invention is characterized by the X-ray diffraction measurement
  • there may be errors in the measurement of the identified peaks sometimes attributable to the equipment or conditions used. More particularly, the 2 theta values may have an error of about ⁇ 0.2, and sometimes an error of about ⁇ 0.1 even if high-tech equipment is used.
  • the measurement error must be taken into account when identifying the structure of the complex.
  • the agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate complex is also characterized by DSC (differential scanning calorimetry) in the spectrum shown in Figure 4, which shows two endotherms: one at about 116 ° C corresponding at the dehydration of the complex, the other at about 238 ° C corresponding to the fusion of the complex.
  • the invention also relates to the agomelatine / benzene sulfonic acid (2/1) complex which is characterized by its powder X-ray diffraction pattern shown in FIG. 5, measured on a Panalytical Xpert P o MPD diffractometer (copper anticathode).
  • the main lines are expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ⁇ 0.2), and relative intensity (expressed as a percentage of the most intense line). are listed in Table 3:
  • Table 3 Table of diffraction peaks of the agomelatine / benzene sulfonic acid complex (2/1) 2-Theta (°) exp. d ( ⁇ ) exp. Intensity (%)
  • the complex of the present invention is characterized by the X-ray diffraction measurement
  • there may be errors in the measurement of the identified peaks sometimes attributable to the equipment or conditions used. More particularly, the 2 theta values may have an error of about ⁇ 0.2, and sometimes an error of about ⁇ 0.1 even if high-tech equipment is used.
  • the measurement error must be taken into account when identifying the structure of the complex.
  • the crystalline structure of the agomelatine / benzene sulfonic acid complex (2/1) was determined and the following parameters were identified:
  • V unit Ci 1712,18900 ⁇
  • the agomelatine / benzene sulfonic acid complex (2/1) is also characterized by DSC (differential scanning calorimetry) in the spectrum shown in Figure 6, which shows an endotherm at about 116 ° C corresponding to the fusion of the complex.
  • the invention also relates to a process for obtaining complexes of agomelatine and sulfonic acids, in which:
  • the two constituents are mixed in an organic or hydro-organic solvent in the desired proportions;
  • the solution obtained is stirred and optionally heated to a temperature at most equal to the boiling point of the chosen solvent;
  • the medium is cooled with stirring and the complex precipitates naturally or precipitates after being taken up in a second solvent;
  • the precipitate obtained is filtered and dried.
  • the solvent used is preferably a ketone such as, for example, acetone; an ether such as, for example, diisopropyl ether, tetrahydrofuran or methyl tert-butyl ether; an aromatic hydrocarbon such as toluene for example.
  • the chosen solvent is an alcohol such as, for example, methanol, ethanol or Fe / Y-butanol; an alkane such as for example w-hexane or "-heptane; or benzonitrile.
  • An alternative method is to co-grind the two components of the co-crystal.
  • the co-grinding is carried out in a steel jrre.
  • a variant of this method consists in adding an organic solvent during grinding; in this case the co-crystal obtained is then dried.
  • solvents used mention will be made more particularly of ketones, for example acetone; or ethers such as, for example, diisopropyl ether or methyl and butyl-butyl ether.
  • Alcohols such as, for example, methanol, ethanol or tert-butanol may also be used.
  • grinding is performed with stainless steel balls.
  • the grinding is carried out by means of vibrations, preferably vibrations with a frequency ranging from 20 to 30 Hz.
  • the vibrations are applied for a duration ranging from 5 minutes to 3 hours.
  • Another alternative method consists in mixing two solutions containing each of the constituents and in rapidly freezing at a very low temperature the mixture obtained, then in drying at this same low temperature the co-crystal thus obtained.
  • the two constituents are mixed in an organic or hydro-organic solvent.
  • the freezing and drying are carried out between -40 ° C and -60 ° C, and more preferably at -40 ° C.
  • Another advantageous process according to the invention consists in mixing the agomelatine powders and the acid in question in a mixer, then extruding it by twin-screw extrusion without a die to obtain a solid grain directly at the extruder outlet.
  • the screw profile used is a high shear profile, optionally with the use of mixing elements to improve the contact surface between the components.
  • the L / D parameter of the screw can vary between 10 and 40. and the speed of rotation between 10 and 200 rpm.
  • the temperature used varies from 40 to 100 ° C.
  • agomelatine and sulfonic acid complexes have significantly increased solubility relative to agomelatine per se, making them more suitable for the preparation of pharmaceutical formulations.
  • the agomelatine and sulphonic acid complexes according to the invention also have excellent stability and very good purity. They are also obtained by a simple process, with no difficult step.
  • the pharmaceutical forms containing the complexes according to the invention will be used for the treatment of disorders of the melatoninergic system, and more particularly in the treatment of stress, sleep disorders, anxiety disorders and in particular generalized anxiety disorder, disorders obsessive compulsive disorder, mood disorders including bipolar disorder, major depression, seasonal depression, cardiovascular diseases, digestive system pathologies, insomnia and fatigue due to jet lag, schizophrenia, panic, melancholy, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as s disorders of the cerebral circulation.
  • the co-crystals according to the invention may be used in sexual dysfunctions, as ovulation inhibitors, immunomodulators and in the treatment of cancers.
  • the invention also extends to pharmaceutical compositions containing as active principle a complex of agomelatine and sulfonic acids according to the invention with one or more adjuvants or excipients.
  • compositions according to the invention mention may be made more particularly of those which are suitable for oral, parenteral (intravenous or subcutaneous), nasal administration, single or coated tablets, granules, sublingual tablets, capsules, tablets, suppositories, creams, ointments, skin gels, injectables, oral suspensions and chewables.
  • the useful dosage is adaptable according to the nature and severity of the condition, the route of administration and the age and weight of the patient. This dosage ranges from 0.1 mg to 1 g per day of agomelatine in one or more doses. Representative examples of the present invention are illustrated with the corresponding Figures to better appreciate the purpose, features, and advantages thereof.
  • Figure 1 powder X-ray diffraction pattern of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) complex of Example 1.
  • Figure 2 DSC thermogram of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) complex of Example 1.
  • Figure 4 DSC thermogram of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate complex of Example 2.
  • FIG. 5 powder X-ray diffraction pattern of the agomelatine / benzene sulfonic acid (2/1) complex of Example 3.
  • FIG. 6 DSC thermogram of the agomelatine / benzene sulfonic acid complex (2/1) of Example 3.
  • Example 1 Agomelatine / 1,5-naphthalene disulfonic acid complex (2/1)
  • Example 2 Agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate complex Mode of operation 1
  • Agomelatine (0.5 g) and 1,5-naphthalene disulfonic acid tetrahydrate (0.370 g) are placed in a non-oxidizable 50 ml jar. Two stainless steel balls 12 mm in diameter are added and the jar is closed. Vibrations having a frequency of 30 Hz are applied for 15 minutes to conduct, after a night of drying at room temperature, 0.805 g of solid.
  • Agomelatine (0.5 g) and 1,5-naphthalene disulfonic acid tetrahydrate (0.370 g) are placed in a non-oxidizable 50 ml jar. Two stainless steel balls 12 mm in diameter are added and the jar is closed. ⁇ of methyl ether and tert-butyl are added. Vibrations with a frequency of 30 Hz are applied for 30 minutes to conduct, after a drying night at room temperature, 0.803g of solid.
  • agomelatine commercially available or prepared according to one of the methods described in the prior art can be used.
  • Solutions at 1 mg / ml of the compounds of the invention are prepared with the mobile phase. 10 ⁇ l of each solution are injected into the liquid chromatography system and the chromatograms are recorded.
  • the compounds of the invention all have purities greater than or equal to 99%.
  • the compounds of the invention are stable under strongly denaturing conditions, which is favorable for their use in pharmaceutical compositions.
  • agomelatine and sulfonic acid complexes of the present invention have a higher solubility to form II agomelatine per se in water, in 0.1N HCl, similar to human gastric fluids, or in a buffer at pH 6.8. These results show that the complexes have a much better potential in terms of bioavailability than form II agomelatine.

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Abstract

Novel complexes of agomelatine and sulphonic acids of formula (I). Drugs.

Description

NOUVEAUX COMPLEXES D'AGOMELATINE ET D'ACIDES SULFONIQUES, NOVEL COMPLEXES OF AGOMELATIN AND SULFONIC ACIDS,
LEUR PROCEDE DE PREPARATION ET LES COMPOSITIONS PHARMACEUTIQUES QUI LES CONTIENNENT PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
La présente invention concerne de nouveaux complexes d'agomélatine et d'acides sulfoniques, leur procédé de préparation ainsi que les compositions pharmaceutiques qui les contiennent. The present invention relates to novel complexes of agomelatine and sulfonic acids, their method of preparation as well as pharmaceutical compositions containing them.
L'agomélatine ou N-[2-(7-méthoxy-l-naphtyl)éthyl]acétamide a la structure de formule (II) : Agomelatine or N- [2- (7-methoxy-1-naphthyl) ethyl] acetamide has the structure of formula (II):
L'agomélatine est commercialisé sous le nom de marque Valdoxan® ou Thymanax® par le groupe français Servier en tant qu'agoniste sur les récepteurs du système mélatoninergique et antagoniste du récepteur 5-HT2c. C'est le premier antidépresseur de type mélatoninergique, utile dans le traitement de la dépression majeure, améliorant le sommeil et la fonction sexuelle. Agomelatine is marketed under the brand name Valdoxan® or Thymanax® by the French group Servier as an agonist of receptors of the melatoninergic system and antagonist of the 5-HT 2C. It is the first melatoninergic antidepressant, useful in the treatment of major depression, improving sleep and sexual function.
L'agomélatine, sa préparation et son utilisation en thérapeutique ont été décrits dans les brevets européens EP 0 447 285 et E I 564202. Agomelatine, its preparation and its therapeutic use have been described in European patents EP 0 447 285 and E I 564202.
L'objet de la présente invention consiste en l'élaboration de complexes d'agomélatine et d'acides sulfoniques ayant la stœchiométrie particulière de 2 équivalents molaires d'agomélatine pour 1 équivalent molaire d'acides sulfoniques. Ces complexes présentent d'excellentes propriétés en matière de solubilité, stabilité et pureté, permettant d'envisager leur utilisation pour la fabrication de compositions pharmaceutiques contenant de l'agomélatine. Par ailleurs, la stœchiométrie des complexes selon la présente invention confère un avantage pondéral en faveur du principe actif du complexe Le. l'agomélatine, permettant d'élaborer des formulations pharmaceutiques contenant de plus faibles quantités de complexe. La présente invention concerne des complexes d'agomélatine et d'acides sulfoniques ayant la structure formule (I) : The object of the present invention is to elaborate complexes of agomelatine and sulfonic acids having the particular stoichiometry of 2 molar equivalents of agomelatine per 1 molar equivalent of sulfonic acids. These complexes have excellent properties in terms of solubility, stability and purity, making it possible to envisage their use for the manufacture of pharmaceutical compositions containing agomelatine. Moreover, the stoichiometry of the complexes according to the present invention confers a weight advantage in favor of the active ingredient of the complex Le. agomelatine, making it possible to develop pharmaceutical formulations containing smaller amounts of complex. The present invention relates to agomelatine and sulfonic acid complexes having the structure of formula (I):
dans laquelle x représente 0 ou 1, et S03H représente l'acide 1 ,5-naphtalène disulfonique ou l'acide benzène sulfonique. wherein x is 0 or 1, and SO 3 H is 1,5-naphthalene disulfonic acid or benzene sulfonic acid.
Les composés préférés selon l'invention sont les complexes d'agomélatine et d'acides sulfoniques suivants : The preferred compounds according to the invention are the following complexes of agomelatine and sulphonic acids:
complexe agomélatine / acide 1,5-naphtalène disulfonique (2/1),  agomelatine complex / 1,5-naphthalene disulfonic acid (2/1),
complexe agomélatine / acide 1 ,5-naphthalène disulfonique (2/1) monohydrate, - complexe agomélatine / acide benzène sulfonique (2/1).  agomelatine complex / 1, 5-naphthalene disulfonic acid (2/1) monohydrate, - agomelatine complex / benzene sulfonic acid (2/1).
Le complexe agomélatine / acide 1,5-naphtalène disulfonique (2/1) est caractérisé par son diagramme de diffraction X sur poudre rprésenté dans la Figure 1 , mesuré sur un diffractomètre Panalytical Xpert Pro MPD (anticathode de cuivre). Les raies principales sont exprimées en termes de distance inter-réticulaire d, d'angle de Bragg 2 thêta (exprimés en °±0,2), et d'intensité relative (exprimée en pourcentage par rapport à la raie la plus intense) et sont listées dans le Tableau 1 : The agomelatine / 1,5-naphthalene disulfonic acid (2/1) complex is characterized by its powder X-ray diffraction pattern shown in FIG. 1, measured on a Panalytical Xpert Pro MPD (copper anticathode) diffractometer. The main lines are expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ± 0.2), and relative intensity (expressed as a percentage of the most intense line). are listed in Table 1:
Tableau 1 : Tableau des pics de diffraction du complexe agomélatine / acide 1,5-naphtalène disulfonique (2/1)  Table 1: Table of diffraction peaks of the complex agomelatine / 1,5-naphthalene disulfonic acid (2/1)
2-Theta (°) exp. d (Â) exp. Intensité (%) 2-Theta (°) exp. d (Â) exp. Intensity (%)
6,3716 13,87229 18,97  6.3716 13.87229 18.97
1 1 ,3804 7,77552 17,98  1 1, 3804 7.77552 17.98
1 1,9227 7,42299 36,06  1 1.9227 7.42299 36.06
12,5064 7,07784 100,00 12,6590 6,99288 13,75 12,5064 7.07784 100.00 12.6590 6.99288 13.75
14,5508 6,08767 44,17  14.5508 6.08767 44.17
15,5658 5,69292 11 ,96  15.5658 5.69292 11, 96
16,2029 5,47051 42,63  16.2029 5.47051 42.63
16,9421 5,23346 25,85  16.9421 5.23346 25.85
17,6267 5,03171 18,67  17.6267 5.03171 18.67
19,4300 4,56857 49,04  19.4300 4.56857 49.04
20,2146 4,39301 22,77  20.2146 4.39301 22.77
21,4353 4,14550 17,80  21.4353 4.1550 17.80
21 ,6713 4,10090 22,84  21, 6713 4.10090 22.84
22,2180 4,00121 64,19  22.2180 4.00121 64.19
22,4174 3,96607 10,83  22.4174 3.96607 10.83
24,0749 3,69664 29,61  24.0749 3.69664 29.61
24,5048 3,63275 13,33  24,5048 3.63275 13.33
25,1744 3,53763 20,58  25.1744 3.53763 20.58
25,7599 3,45853 23,59  25.7599 3.45853 23.59
Lorsque le complexe de la présente invention est caractérisé par la mesure de diffraction aux rayons X, il peut y avoir des erreurs de mesure des pics identifiés parfois attribuables à l'équipement ou aux conditions utilisées. Plus particulièrement, les valeurs 2 thêta peuvent avoir une erreur d'environ ± 0,2, et parfois une erreur d'environ ± 0,1 même si des équipements de haute technicité sont utilisés. Ainsi, l'erreur de mesure doit être prise en compte lors de l'identification de la structure du complexe. When the complex of the present invention is characterized by the X-ray diffraction measurement, there may be errors in the measurement of the identified peaks sometimes attributable to the equipment or conditions used. More particularly, the 2 theta values may have an error of about ± 0.2, and sometimes an error of about ± 0.1 even if high-tech equipment is used. Thus, the measurement error must be taken into account when identifying the structure of the complex.
La structure cristalline du complexe agomélatine / acide 1 ,5-naphtalène disulfonique (2/1) a été déterminée et les paramètres suivants ont été identifiés: The crystal structure of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) complex was determined and the following parameters were identified:
Groupe d'espace : P 1 21/c 1 (14)  Space group: P 1 21 / c 1 (14)
- Paramètres de maille: a = 8,4970(3 )A, b = 8,0873(3)A, c = 27,7107(9)Â; = 90°, β = 93.059(2)°, γ = 90°  - Mesh parameters: a = 8.4970 (3) A, b = 8.0873 (3) A, c = 27.7107 (9) Å; = 90 °, β = 93.059 (2) °, γ = 90 °
- Volume de la maille : Vimit ce,t = 1901 ,51100Â3 Le complexe agomélatine / acide 1 ,5-naphtalène disulfonique (2/1) est égaleme t caractérisé par DSC (differential scanning calorimetry) dans le spectre représenté dans la Figure 2, qui montre un endotherme correspondant à la fusion du complexe à une température d'environ 237°C. - Volume of the mesh: V imit this , t = 1901, 51100 3 The agomelatine / 1,5-naphthalene disulfonic acid complex (2/1) is also characterized by DSC (differential scanning calorimetry) in the spectrum shown in Figure 2, which shows an endotherm corresponding to the fusion of the complex at a temperature of about 237 ° C.
L'invention concerne également le complexe agomélatine / acide 1,5-naphthalène disulfonique (2/1) monohydrate qui est caractérisé par son diagramme de diffraction X sur poudre représenté dans la Figure 3, mesuré sur un diffractomètre Panalytical Xpert Pro MPD (anticathode de cuivre). Les raies principales sont exprimées en tennes de distance inter-réticulaire d, d'angle de Bragg 2 thêta (exprimés en °±0,2), et d'intensité relative (exprimée en pourcentage par rapport à la raie la plus intense) et sont listées dans le Tableau 2: The invention also relates to the complex agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate which is characterized by its powder X-ray diffraction pattern shown in Figure 3, measured on a Panalytical Xpert Pro MPD (anticathode) diffractometer. copper). The main lines are expressed as inter-reticular distance d, Bragg angle 2 theta (expressed in ± 0.2), and relative intensity (expressed as a percentage of the most intense line). are listed in Table 2:
Tableau 2: Tableau des pics de diffraction du complexe agomélatine / acide 1,5- naphthalène disulfonique (2/1) monohydrate  Table 2: Table of diffraction peaks of the complex agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate
2-Theta (°) exp. d (À) exp. Intensité (%)  2-Theta (°) exp. d (To) exp. Intensity (%)
9,6680 9,14852 12,45  9.6680 9.14852 12.45
12,4885 7,08796 57,23  12.4885 7.08796 57.23
12,6164 7,01639 28,61  12.6164 7.01639 28.61
14,5042 6,10715 57,42  14,5042 6,10715 57.42
16,2684 5,44863 25,67  16.2684 5.44863 25.67
16,4624 5,38484 32,93  16.4624 5.38484 32.93
16,8967 5,24739 90,90  16.8967 5.24739 90.90
19,3772 4,58091 10,50  19.3772 4.58091 10.50
22,4767 3,95573 100,00 22.4767 3.95573 100.00
23,4111 3,79992 20,49 23.4111 3.79992 20.49
23,5330 3,78051 44,02  23.5330 3.78051 44.02
23,6735 3,75840 21,92  23.6735 3.75840 21.92
24,0477 3,70076 13,67  24.0477 3.70076 13.67
24,5716 3,62303 13,43  24.5716 3.62303 13.43
25,1240 3,54460 12,46  25.1404 3.54460 12.46
26,6602 3,34374 19,10  26.6602 3.34374 19.10
28,1333 3,16930 12,07 28,2443 3,15971 22,49 28.1333 3.16930 12.07 28.2443 3.15971 22.49
Lorsque le complexe de la présente invention est caractérisé par la mesure de diffraction aux rayons X, il peut y avoir des erreurs de mesure des pics identifiés parfois attribuables à l'équipement ou aux conditions utilisées. Plus particulièrement, les valeurs 2 thêta peuvent avoir une erreur d'environ ± 0,2, et parfois une erreur d'environ ± 0,1 même si des équipements de haute technicité sont utilisés. Ainsi, l'erreur de mesure doit être prise en compte lors de l'identification de la structure du complexe. When the complex of the present invention is characterized by the X-ray diffraction measurement, there may be errors in the measurement of the identified peaks sometimes attributable to the equipment or conditions used. More particularly, the 2 theta values may have an error of about ± 0.2, and sometimes an error of about ± 0.1 even if high-tech equipment is used. Thus, the measurement error must be taken into account when identifying the structure of the complex.
La structure cristalline du complexe agomélatine / acide 1,5-naphtalène disulfonique (2/1) monohydrate a été déterminée et les paramètres suivants ont été identifiés: The crystal structure of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate complex was determined and the following parameters were identified:
- Groupe d'espace : P -1 (2)  - Space group: P -1 (2)
- Paramètres de maille: a = 9,5673(3) Â, b = 9,7223(3) Â, c = 1 1 ,4632(3) Â; a =  - Mesh parameters: a = 9.5673 (3) Å, b = 9.7223 (3) Å, c = 11, 4632 (3) Å; a =
76,967(2)°, β = 75,339(1)°, γ = 78,675(2)°  76.967 (2) °, β = 75.339 (1) °, γ = 78.675 (2) °
- Volume de la maille : Vunit «n = 993,93800 Â3 - Volume of the mesh: V a i t " n = 993.93800 Â 3
Le complexe agomélatine / acide 1,5-naphtalène disulfonique (2/1) monohydrate est également caractérisé par DSC (differential scanning calorimetry) dans le spectre représenté dans la Figure 4, qui montre deux endothermes : l'un à environ 116°C correspondant à la déshydratation du complexe, l'autre à environ 238°C correspondant à la fusion du complexe. The agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate complex is also characterized by DSC (differential scanning calorimetry) in the spectrum shown in Figure 4, which shows two endotherms: one at about 116 ° C corresponding at the dehydration of the complex, the other at about 238 ° C corresponding to the fusion of the complex.
L'invention concerne également le complexe agomélatine / acide benzène sulfonique (2/1) qui est caractérisé par son diagramme de diffraction X sur poudre représenté dans la Figure 5, mesuré sur un diffractomètre Panalytical Xpert P o MPD (anticathode de cuivre). Les raies principales sont exprimées en termes de distance inter-réticulaire d, d'angle de Bragg 2 thêta (exprimés en °±0,2), et d'intensité relative (exprimée en pourcentage par rapport à la raie la plus intense) et sont listées dans le Tableau 3 : The invention also relates to the agomelatine / benzene sulfonic acid (2/1) complex which is characterized by its powder X-ray diffraction pattern shown in FIG. 5, measured on a Panalytical Xpert P o MPD diffractometer (copper anticathode). The main lines are expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ± 0.2), and relative intensity (expressed as a percentage of the most intense line). are listed in Table 3:
Tableau 3: Tableau des pics de diffraction du complexe agomélatine / acide benzène sulfonique (2/1) 2-Theta (°) exp. d (Â) exp. Intensité (%) Table 3: Table of diffraction peaks of the agomelatine / benzene sulfonic acid complex (2/1) 2-Theta (°) exp. d (Â) exp. Intensity (%)
8,0711 10,95469 35,25  8.0717 10.95469 35.25
12,6820 6,98026 68,37  12.6820 6.98026 68.37
12,7706 6,93203 65,37  12.7706 6.93203 65.37
13,01 14 6,80427 15,18  13.01 14 6.80427 15.18
13,3054 6,65458 31,84  13.3054 6.65458 31.84
14,9475 5,92700 19,42  14.9475 5.92700 19.42
15,1121 5,86283 70,19  15.1121 5.86283 70.19
15,4873 5,72160 14,16  15.4873 5.72160 14.16
16,1644 5,48344 12,98  16.1644 5.48344 12.98
17,2360 5,14486 21,06  17.2360 5.14486 21.06
18,1046 4,89993 36,33  18.1046 4.89993 36.33
18,6255 4,76406 10,91  18.6255 4.76406 10.91
18,8009 4,72001 33,43  18.8009 4.72001 33.43
20,0908 4,41978 30,26  20.0908 4.41978 30.26
20,4742 4,33788 42,37  20.4742 4.37788 42.37
20,6921 4,29270 56,78  20.6921 4.29270 56.78
20,8640 4,25771 26,42  20.8640 4.25771 26.42
21,7142 4,09289 13,88  21.7142 4.09289 13.88
23,3683 3,80679 15,16  23.3683 3.80679 15.16
23,6410 3,76349 100,00  23.6410 3.76349 100.00
24,9314 3,57154 26,81  24.9314 3.57154 26.81
25,6543 3,47253 10,71  25.6543 3.47253 10.71
27,5599 3,23660 14,00  27.5599 3.23660 14.00
Lorsque le complexe de la présente invention est caractérisé par la mesure de diffraction aux rayons X, il peut y avoir des erreurs de mesure des pics identifiés parfois attribuables à l'équipement ou aux conditions utilisées. Plus particulièrement, les valeurs 2 thêta peuvent avoir une erreur d'environ ± 0,2, et parfois une erreur d'environ ± 0,1 même si des équipements de haute technicité sont utilisés. Ainsi, l'erreur de mesure doit être prise en compte lors de l'identification de la structure du complexe. La structure cristalline du complexe agomélatine / acide benzène sulfonique (2/1) a été déterminée et les paramètres suivants ont été identifiés: When the complex of the present invention is characterized by the X-ray diffraction measurement, there may be errors in the measurement of the identified peaks sometimes attributable to the equipment or conditions used. More particularly, the 2 theta values may have an error of about ± 0.2, and sometimes an error of about ± 0.1 even if high-tech equipment is used. Thus, the measurement error must be taken into account when identifying the structure of the complex. The crystalline structure of the agomelatine / benzene sulfonic acid complex (2/1) was determined and the following parameters were identified:
Groupe d'espace : P -1 (2)  Space group: P -1 (2)
- Paramètres de maille: a = 15,5878(8) Â, b = 15,7088(6) Â, c = 7,2091(3) A; a = 100,445(2)°, p = 99,470(2)°, γ = 89,054(3)°  - Mesh parameters: a = 15.5878 (8) Å, b = 15.7088 (6) Å, c = 7.2091 (3) A; a = 100.445 (2) °, p = 99.470 (2) °, γ = 89.054 (3) °
- Volume de la maille : Vunit ceii = 1712,18900 Â - Volume of the mesh: V unit ceii = 1712,18900 Â
Le complexe agomélatine / acide benzène sulfonique (2/1) est également caractérisé par DSC (differential scanning calorimetry) dans le spectre représenté dans la Figure 6, qui montre un endotherme à environ 116°C correspondant à la fusion du complexe. L'invention concerne également un procédé d'obtention des complexes d'agomélatine et d'acides sulfoniques, dans lequel : The agomelatine / benzene sulfonic acid complex (2/1) is also characterized by DSC (differential scanning calorimetry) in the spectrum shown in Figure 6, which shows an endotherm at about 116 ° C corresponding to the fusion of the complex. The invention also relates to a process for obtaining complexes of agomelatine and sulfonic acids, in which:
les deux constituants sont mélangés au sein d'un solvant organique ou hydro- organique dans les proportions désirées;  the two constituents are mixed in an organic or hydro-organic solvent in the desired proportions;
la solution obtenue est agitée et optionnellement chauffée à une température au plus égale à la température d'ébullition du solvant choisi ;  the solution obtained is stirred and optionally heated to a temperature at most equal to the boiling point of the chosen solvent;
le milieu est refroidi sous agitation et le complexe précipite naturellement ou précipite après reprise dans un deuxième solvant ;  the medium is cooled with stirring and the complex precipitates naturally or precipitates after being taken up in a second solvent;
le précipité obtenu est filtré et séché.  the precipitate obtained is filtered and dried.
Dans le procédé selon l'invention, le solvant utilisé est préférentiellement une cétone comme par exemple l'acétone ; un éther comme par exemple Péther diisopropylique, le tétrahydrofurane ou l' éther de méthyle et de tert-butyle ; un hydrocarbure aromatique comme le toluène par exemple. Lorsqu'un deuxième solvant est utilisé pour favoriser la précipitation du complexe, le solvant choisi est un alcool comme par exemple le méthanol, l'éthanol ou le fe/Y-butanol ; un alkane comme par exemple le w-hexane ou le «-heptane ; ou le benzonitriîe. In the process according to the invention, the solvent used is preferably a ketone such as, for example, acetone; an ether such as, for example, diisopropyl ether, tetrahydrofuran or methyl tert-butyl ether; an aromatic hydrocarbon such as toluene for example. When a second solvent is used to promote the precipitation of the complex, the chosen solvent is an alcohol such as, for example, methanol, ethanol or Fe / Y-butanol; an alkane such as for example w-hexane or "-heptane; or benzonitrile.
Un procédé alternatif consiste à co-broyer les deux constituants du co-cristal. Préférentiellement le co -broyage est effectué dans une j rre en acier. Une variante de ce procédé consiste à rajouter un solvant organique lors du broyage ; dans ce cas le co-cristal obtenu est ensuite séché. Parmi les solvants utilisés on citera plus particulièrement les cétones comme par exemple l'acétone ; ou les éthers comme par exemple Péther diisopropylique, ou Péther de méthyle et de /eri-butyle. Les alcools comme par exemple le méthanol l'éthanol ou le tert-butanoi peuvent également être utilisés. An alternative method is to co-grind the two components of the co-crystal. Preferably the co-grinding is carried out in a steel jrre. A variant of this method consists in adding an organic solvent during grinding; in this case the co-crystal obtained is then dried. Among the solvents used, mention will be made more particularly of ketones, for example acetone; or ethers such as, for example, diisopropyl ether or methyl and butyl-butyl ether. Alcohols such as, for example, methanol, ethanol or tert-butanol may also be used.
Avantageusement, le broyage est réalisé avec des billes en inox. Le broyage est réalisé au moyen de vibrations, préférentiellement des vibrations avec une fréquence allant de 20 à 30 Hz. Les vibrations sont appliquées pendant une durée pouvant aller de 5 minutes à 3 heures. Advantageously, grinding is performed with stainless steel balls. The grinding is carried out by means of vibrations, preferably vibrations with a frequency ranging from 20 to 30 Hz. The vibrations are applied for a duration ranging from 5 minutes to 3 hours.
Un autre procédé alternatif consiste à mélanger deux solutions contenant chacun des constituants et à congeler rapidement à très basse température le mélange obtenu, puis à sécher à cette même basse température le co-cristal ainsi obtenu. Avantageusement, les deux constituants sont mélangés au sein d'un solvant organique ou hydro -organique. De façon préférée, la congélation et le séchage sont effectués entre -40°C et -60°C, et plus préférentiellement à -40°C. Another alternative method consists in mixing two solutions containing each of the constituents and in rapidly freezing at a very low temperature the mixture obtained, then in drying at this same low temperature the co-crystal thus obtained. Advantageously, the two constituents are mixed in an organic or hydro-organic solvent. Preferably, the freezing and drying are carried out between -40 ° C and -60 ° C, and more preferably at -40 ° C.
Un autre procédé avantageux selon l'invention consiste à mélanger les poudres d'agomélatine et de l'acide considéré dans un mélangeur, puis à l'extruder par extrusion bi-vis sans filière pour obtenir un grain solide directement en sortie d'extrudeuse. De préférence, le profil de vis utilisé est un profil à fort cisaillement, avec optionnellement l'utilisation d'éléments malaxeurs permettant d'améliorer la surface de contact entre les constituants, Le paramètre L/D de la vis peut varier entre 10 et 40 et la vitesse de rotation entre 10 et 200 tr/min. La température utilisée varie de 40 à 100 °C. Another advantageous process according to the invention consists in mixing the agomelatine powders and the acid in question in a mixer, then extruding it by twin-screw extrusion without a die to obtain a solid grain directly at the extruder outlet. Preferably, the screw profile used is a high shear profile, optionally with the use of mixing elements to improve the contact surface between the components. The L / D parameter of the screw can vary between 10 and 40. and the speed of rotation between 10 and 200 rpm. The temperature used varies from 40 to 100 ° C.
Les complexes d'agomélatine et d'acides sulfoniques obtenus ont une solubilité accrue de façon très significative par rapport à agomélatine per se, ce qui les rend plus appropriés pour l'élaboration de formulations pharmaceutiques. Les complexes d'agomélatine et d'acides sulfoniques selon l'invention présentent de plus une excellente stabilité et une très bonne pureté. Ils sont par ailleurs obtenus par un procédé simple, ne comportant aucune étape difficile. Les formes pharmaceutiques contenant les complexes selon l'invention seront utilisées pour le traitement des désordres du système mélatoninergique, et plus particulièrement dans le traitement du stress, des troubles du sommeil, des troubles de l'anxiété et notamment du trouble anxiété généralisée, des troubles obsessionnels compulsifs, des troubles de l'humeur et notamment des troubles bipolaires, de la dépression majeure, des dépressions saisonnières, des pathologies cardiovasculaires, des pathologies du système digestif, des insomnies et fatigues dues aux décalages horaires, de la schizophrénie, des attaques de panique, de la mélancolie, des troubles de l'appétit, de l'obésité, de l'insomnie, de la douleur, des troubles psychotiques, de l'épilepsie, du diabète, de la maladie de Parkinson, de la démence sénile, des divers désordres liés au vieillissement normal ou pathologique, de la migraine, des pertes de mémoire, de la maladie d'Alzheimer, ainsi que dans les troubles de la circulation cérébrale. Dans un autre domaine d'activité, les co- cristaux selon l'invention pourront être utilisés dans les dysfonctionnements sexuels, en tant qu'inhibiteurs de l'ovulation, immunomodulateurs et dans le traitement des cancers. L'invention s'étend aussi aux compositions pharmaceutiques renfermant comme principe actif un complexe d'agomélatine et d'acides sulfoniques selon l'invention avec un ou plusieurs adjuvants ou excipients. The resulting agomelatine and sulfonic acid complexes have significantly increased solubility relative to agomelatine per se, making them more suitable for the preparation of pharmaceutical formulations. The agomelatine and sulphonic acid complexes according to the invention also have excellent stability and very good purity. They are also obtained by a simple process, with no difficult step. The pharmaceutical forms containing the complexes according to the invention will be used for the treatment of disorders of the melatoninergic system, and more particularly in the treatment of stress, sleep disorders, anxiety disorders and in particular generalized anxiety disorder, disorders obsessive compulsive disorder, mood disorders including bipolar disorder, major depression, seasonal depression, cardiovascular diseases, digestive system pathologies, insomnia and fatigue due to jet lag, schizophrenia, panic, melancholy, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as s disorders of the cerebral circulation. In another field of activity, the co-crystals according to the invention may be used in sexual dysfunctions, as ovulation inhibitors, immunomodulators and in the treatment of cancers. The invention also extends to pharmaceutical compositions containing as active principle a complex of agomelatine and sulfonic acids according to the invention with one or more adjuvants or excipients.
Parmi les compositions pharmaceutiques selon l'invention, on pourra citer plus particulièrement celles qui conviennent pour l'administration orale, parentérale (intraveineuse ou sous-cutanée), nasale, les comprimés simples ou dragéifiés, les granulés, les comprimés sublinguaux, les gélules, les tablettes, les suppositoires, les crèmes, les pommades, les gels dermiques, les préparations injectables, les suspensions buvables et les pâtes à mâcher. Among the pharmaceutical compositions according to the invention, mention may be made more particularly of those which are suitable for oral, parenteral (intravenous or subcutaneous), nasal administration, single or coated tablets, granules, sublingual tablets, capsules, tablets, suppositories, creams, ointments, skin gels, injectables, oral suspensions and chewables.
La posologie utile est adaptable selon la nature et la sévérité de l'affection, la voie d'administration ainsi que l'âge et le poids du patient. Cette posologie varie de 0,1 mg à 1 g par jour d'agomélatine en une ou plusieurs prises. Des exemples représentatifs de la présente invention sont illustrés avec les Figures correspondantes afin de mieux en apprécier l'objet, les caractéristiques, et les avantages. The useful dosage is adaptable according to the nature and severity of the condition, the route of administration and the age and weight of the patient. This dosage ranges from 0.1 mg to 1 g per day of agomelatine in one or more doses. Representative examples of the present invention are illustrated with the corresponding Figures to better appreciate the purpose, features, and advantages thereof.
Figure 1 : diagramme de diffraction X sur poudre du complexe agomélatine / acide 1 ,5- naphtalène disulfonique (2/1) de l'Exemple 1. Figure 1: powder X-ray diffraction pattern of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) complex of Example 1.
Figure 2 : thermogramme DSC du complexe agomélatine / acide 1 ,5-naphtalène disulfonique (2/1) de l'Exemple 1.  Figure 2: DSC thermogram of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) complex of Example 1.
Figure 3 : diagramme de diffraction X sur poudre du complexe agomélatine / acide 1,5- naphtalène disulfonique (2/1) monohydrate de l'Exemple 2.  3: powder X-ray diffraction diagram of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate complex of Example 2.
Figure 4 : thermogramme DSC du complexe agomélatine / acide 1,5-naphtalène disulfonique (2/1) monohydrate de l'Exemple 2.  Figure 4: DSC thermogram of the agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate complex of Example 2.
Figure 5 : diagramme de diffraction X sur poudre du complexe agomélatine / acide benzène suifonique (2/1) de l'Exemple 3.  FIG. 5: powder X-ray diffraction pattern of the agomelatine / benzene sulfonic acid (2/1) complex of Example 3.
Figure 6 : thermogramme DSC du complexe agomélatine / acide benzène suifonique (2/1) de l'Exemple 3. Exemple 1 : Complexe agomélatine / acide 1,5-naphtalène disulfonique (2/1)  FIG. 6: DSC thermogram of the agomelatine / benzene sulfonic acid complex (2/1) of Example 3. Example 1: Agomelatine / 1,5-naphthalene disulfonic acid complex (2/1)
Mode-opératoire 1 Operating mode 1
L' agomélatine (5,00g, 2 eq) et l'acide 1 ,5-naphtalène disulfonique anhydre (2,96g, 1 eq) sont placés dans un réacteur. 20ml d'acétone sont ajoutés. La suspension est agitée sous reflux pendant 1 heure, puis immédiatement filtrée. Le gâteau est lavé 2 fois à l'acétone, puis séché pendant 1 heure. 25g d'un solide blanc correspondant au produit du titre sont obtenus.  Agomelatine (5.00 g, 2 eq) and anhydrous 1,5-naphthalenesulphonic acid (2.96 g, 1 eq) are placed in a reactor. 20ml of acetone are added. The suspension is stirred under reflux for 1 hour, then immediately filtered. The cake is washed twice with acetone and then dried for 1 hour. 25 g of a white solid corresponding to the title product are obtained.
Rendement: 78,5%  Yield: 78.5%
Point de fusion : 237°C Melting point: 237 ° C
Mode-opératoire 2 Operating mode 2
L'agomélatine (2,98g, 2 eq) et l'acide 1,5-naphtalène disulfonique tétrahydrate (2,18g, 1 eq) sont introduits dans un ballon de 250 ml. 100 ml d'acétone sont ajoutés et le milieu réactionnel est porté au reflux pendant 3 heures (la cristallisation se produit au bout d'une heure environ). La suspension est refroidie à température ambiante et agitée pendant 1 heure. 4,03g d'un solide blanc correspondant au produit du titre sont isolés par filtration et séchés sous vide (10 mbars) à 40°C pendant 15 heures. Agomelatine (2.98 g, 2 eq) and 1,5-naphthalene disulfonic acid tetrahydrate (2.18 g, 1 eq) are introduced into a 250 ml flask. 100 ml of acetone are added and the reaction mixture is refluxed for 3 hours (the crystallization occurs after about one hour). The suspension is cooled to room temperature and stirred for 1 hour. hour. 4.03 g of a white solid corresponding to the title product are isolated by filtration and dried under vacuum (10 mbar) at 40 ° C. for 15 hours.
Rendement : 85,0% Yield: 85.0%
Point de fusion : 237°C Mode-opératoire 3 Melting Point: 237 ° C Operating Mode 3
L'agomélatine (5,00g, 2 eq) et l'acide 1,5-naphtalène disulfonique anhydre (2,96g, 1 eq) sont placés dans un réacteur. 40ml d'éther de méthyle et de tert-butyle sont ajoutés. La suspension est agitée sous reflux pendant 3 heures, puis immédiatement filtrée. Le gâteau est lavé 2 fois à l'éther de méthyle et de tert-butyle, puis séché pendant 1 heure. 5,28g d'un solide blanc correspondant au produit du titre sont obtenus.  Agomelatine (5.00 g, 2 eq) and anhydrous 1,5-naphthalenesulphonic acid (2.96 g, 1 eq) are placed in a reactor. 40 ml of methyl ether and tert-butyl are added. The suspension is stirred under reflux for 3 hours, then immediately filtered. The cake is washed twice with methyl tert-butyl ether and then dried for 1 hour. 5.28 g of a white solid corresponding to the title product are obtained.
Rendement: 66,3% Yield: 66.3%
Point de fusion : 237°C Melting point: 237 ° C
Exemple 2 : Complexe agomélatine / acide 1,5-naphtalène disulfonique (2/1) monohydrate Mode-opératoire 1 Example 2: Agomelatine / 1,5-naphthalene disulfonic acid (2/1) monohydrate complex Mode of operation 1
L'agomélatine (5,00g, 1 eq) et l'acide 1,5-naphtalène disulfonique anhydre (5,92g, 1 eq) sont placés dans un réacteur. 10ml d'éthanol et 20ml d'eau sont ajoutés. La suspension est agitée sous reflux pendant 0,5 heure afin qu'elle devienne limpide. Le milieu est ensuite refroidi naturellement sous agitation pendant 0,5 heure, et la suspension est filtrée. Le gâteau est lavé avec de l'éthanol et de l'eau, puis séché pendant 1 heure. 5,15g d'un solide blanc sont obtenus.  Agomelatine (5.00 g, 1 eq) and anhydrous 1,5-naphthalenesulphonic acid (5.92 g, 1 eq) are placed in a reactor. 10ml of ethanol and 20ml of water are added. The suspension is stirred under reflux for 0.5 hours to become clear. The medium is then cooled naturally with stirring for 0.5 hours, and the suspension is filtered. The cake is washed with ethanol and water and then dried for 1 hour. 5.15 g of a white solid are obtained.
Rendement: 63,2% Yield: 63.2%
Point de fusion : 116°C (endotherme de déshydratation), 238°C Mode-opératoire 2  Melting point: 116 ° C (dehydration endotherm), 238 ° C Operating Mode 2
L'agomélatine (5,00g, 1 eq) et l'acide 1,5-naphtalène disulfonique tétrahydrate (7,40g, 1 eq) sont introduits dans un réacteur. 10ml d'éthanol et 20ml d'eau sont ajoutés. La suspension est agitée sous reflux pendant 0,5 heure afin qu'elle devienne limpide. Le milieu est ensuite refroidi naturellement sous agitation pendant 0,5 heure, et la suspension est filtrée. Le gâteau est lavé avec de l'éthanol et de l'eau, puis séché pendant 1 heure. 4,90g d'un solide blanc sont obtenus. Agomelatine (5.00 g, 1 eq) and 1,5-naphthalene disulfonic acid tetrahydrate (7.40 g, 1 eq) are introduced into a reactor. 10ml of ethanol and 20ml of water are added. The suspension is stirred under reflux for 0.5 hours to become clear. The The medium is then cooled naturally with stirring for 0.5 hours, and the suspension is filtered. The cake is washed with ethanol and water and then dried for 1 hour. 4.90 g of a white solid are obtained.
Rendement : 60,2%  Yield: 60.2%
Point de fusion : 1 16°C (endotherme de déshydratation), 238°C Mode-opératoire 3  Melting point: 16 ° C (dehydration endotherm), 238 ° C Operating Mode 3
L'agomélatine (0,5g) et l'acide 1 ,5-naphtalène disulfonique tétrahydrate (0,370g) sont placés dans une jarre de 50ml non oxydable. Deux billes en acier inox de 12 mm de diamètre sont ajoutées et la jarre est fermée. Des vibrations ayant une fréquence de 30 Hz sont appliquées pendant 15 minutes pour conduire, après une nuit de séchage à température ambiante, à 0,805g de solide.  Agomelatine (0.5 g) and 1,5-naphthalene disulfonic acid tetrahydrate (0.370 g) are placed in a non-oxidizable 50 ml jar. Two stainless steel balls 12 mm in diameter are added and the jar is closed. Vibrations having a frequency of 30 Hz are applied for 15 minutes to conduct, after a night of drying at room temperature, 0.805 g of solid.
Point de fusion : 1 16°C (endotherme de déshydratation), 238°C Mode-opératoire 4  Melting point: 16 ° C (dehydration endotherm), 238 ° C Mode of operation 4
L'agomélatine (0,5g) et l'acide 1,5-naphtalène disulfonique tétrahydrate (0,370g) sont placés dans une jarre de 50ml non oxydable. Deux billes en acier inox de 12 mm de diamètre sont ajoutées et la jarre est fermée. ΙΟΟμΙ d'éther de méthyle et de tert-butyle sont ajoutés. Des vibrations ayant une fréquence de 30 Hz sont appliquées pendant 30 minutes pour conduire, après une nuit de séchage à température ambiante, à 0,803g de solide.  Agomelatine (0.5 g) and 1,5-naphthalene disulfonic acid tetrahydrate (0.370 g) are placed in a non-oxidizable 50 ml jar. Two stainless steel balls 12 mm in diameter are added and the jar is closed. ΙΟΟμΙ of methyl ether and tert-butyl are added. Vibrations with a frequency of 30 Hz are applied for 30 minutes to conduct, after a drying night at room temperature, 0.803g of solid.
Point de fusion : 1 16°C (endotherme de déshydratation), 238°C Melting point: 16 ° C (dehydration endotherm), 238 ° C
Exemple 3 : Complexe agomélatine / acide benzène sulfonique (2/1) Example 3 Agomelatine Complex / Benzene Sulfonic Acid (2/1)
L'agomélatine (5,00g, 2 eq) et l'acide benzène sulfonique (1,62g, 1 eq) sont introduits dans un réacteur. 10ml d'éthanol et 15ml (10ml + 5ml) de toluène sont ajoutés. La suspension est agitée sous reflux pendant 0,5 heure afin qu'elle devienne claire (si la solution n'est pas limpide, on rajoute de l'éthanol jusqu'à ce qu'elle le devienne). Le milieu est ensuite refroidi naturellement jusqu'à 5°C sous agitation pendant 0,5 heure, et la suspension est filtrée. Le gâteau est séché pendant 1 heure. 4,31g d'un solide blanc correspondant au produit du titre sont obtenus.  Agomelatine (5.00 g, 2 eq) and benzenesulphonic acid (1.62 g, 1 eq) are introduced into a reactor. 10ml of ethanol and 15ml (10ml + 5ml) of toluene are added. The suspension is stirred under reflux for 0.5 hours so that it becomes clear (if the solution is not clear, we add ethanol until it becomes). The medium is then cooled naturally to 5 ° C. with stirring for 0.5 hours, and the suspension is filtered. The cake is dried for 1 hour. 4.31 g of a white solid corresponding to the title product are obtained.
Rendement : 65,2% Point de fusion : 1 16°C Yield: 65.2% Melting point: 1 16 ° C
Dans les exemples ci-dessus, on peut utiliser l'agomélatine disponible dans le commerce ou préparé selon une des méthodes décrites dans l'art antérieur. In the examples above, agomelatine commercially available or prepared according to one of the methods described in the prior art can be used.
Exemple 4 : Compositions pharmaceutiques : gélules dosées à 25 mg d'agomélatineEXAMPLE 4 Pharmaceutical Compositions: Capsules Assayed at 25 mg Agomelatine
Composition pharmaceutique contenant le composé de l'Exemple 1 Pharmaceutical composition containing the compound of Example 1
Formulation pour la préparation de 1000 gélules  Formulation for the preparation of 1000 capsules
contenant chacune 25 mg d'agomélatine  each containing 25 mg of agomelatine
Composé de l'Exemple 1 39,8 g  Compound of Example 1 39.8 g
Lactose (Spherolac 100) 85,2 g  Lactose (Spherolac 100) 85.2 g
Amidon 1500 25,5 g  Starch 1500 25.5 g
CMS-Na 8,5 g  CMS-Na 8.5 g
Ac-Di-Sol ® (FMC) 17 g  Ac-Di-Sol ® (FMC) 17 g
Acide Stéarique 3,4 g  Stearic acid 3.4 g
Composition pharmaceutique contenant le composé de l'Exemple 2 Pharmaceutical composition containing the compound of Example 2
Formulation pour la préparation de 1000 gélules  Formulation for the preparation of 1000 capsules
contenant chacune 25 mg d'agomélatine  each containing 25 mg of agomelatine
Composé de l'Exemple 2 40,7 g  Compound of Example 2 40.7 g
Lactose (Spherolac 100) 85,2 g  Lactose (Spherolac 100) 85.2 g
Amidon 1500 25,5 g  Starch 1500 25.5 g
CMS-Na 8,5 g  CMS-Na 8.5 g
Ac-Di-Sol ® (FMC) 17 g  Ac-Di-Sol ® (FMC) 17 g
Acide Stéarique 3,4 g  Stearic acid 3.4 g
Composition pharmaceutique contenant le composé de l'Exemple 3 Pharmaceutical composition containing the compound of Example 3
Formulation pour la préparation de 1000 gélules  Formulation for the preparation of 1000 capsules
contenant chacune 25 mg d'agomélatine  each containing 25 mg of agomelatine
Composé de l'Exemple 3 33,1 g  Compound of Example 3 33.1 g
Lactose (Spherolac 00) 85,2 g  Lactose (Spherolac 00) 85.2 g
Amidon 1500 25,5 g  Starch 1500 25.5 g
CMS-Na 8,5 g  CMS-Na 8.5 g
Ac-Di-Sol ® (FMC) 17 g  Ac-Di-Sol ® (FMC) 17 g
Acide Stéarique 3,4 g Exemple 5 : Compositions pharmaceutiques : comprimés dosés à 25 mg Stearic acid 3.4 g Example 5: Pharmaceutical Compositions: 25 mg Tablets
d'agomélatine agomelatine
Formulation pour la préparation de 1000 comprimés contenant chacun 25 mg d'agomélatine: Formulation for the preparation of 1000 tablets each containing 25 mg of agomelatine:
Composé de l'Exemple 1 39,8 gCompound of Example 1 39.8 g
Lactose monohydrate 1 5 gLactose monohydrate 1 5 g
Stéarate de Magnésium 2 gMagnesium Stearate 2 g
Amidon de maïs 33 gCorn starch 33 g
Maltodextrines 15 g Silice colloïdale anhydre lMaltodextrins 15 g Colloidal anhydrous silica
Amidon de maïs prégélatinisé, Type A 9 g Pregelatinized corn starch, Type A 9 g
Formulation pour la préparation de 1000 comprimés contenant chacun 25 mg d'agomélatine: Formulation for the preparation of 1000 tablets each containing 25 mg of agomelatine:
Composé de l'Exemple 2 40,7 g Lactose monohydrate 115 g Compound of Example 2 40.7 g Lactose monohydrate 115 g
Stéarate de Magnésium 2 gMagnesium Stearate 2 g
Amidon de maïs 33 gCorn starch 33 g
Maltodextrins 15 gMaltodextrins 15 g
Silice colloïdale anhydre 1 g Amidon de maïs prégélatinisé, Type A 9 g Anhydrous Colloidal Silica 1 g Pregelatinized Maize Starch, Type A 9 g
Formulation pour la préparation de 1000 comprimés contenant chacun 25 mg d'agomélatine: Formulation for the preparation of 1000 tablets each containing 25 mg of agomelatine:
Composé de l'Exemple 3 33,1 g Compound of Example 3 33.1 g
Lactose monohydrate 115 g Stéarate de Magnésium 2 gLactose monohydrate 115 g Magnesium stearate 2 g
Amidon de maïs 33 gCorn starch 33 g
Maltodextrins 15 gMaltodextrins 15 g
Silice colloïdale anhydre 1 gAnhydrous colloidal silica 1 g
Amidon de maïs prégélatinisé, Type A 9 g Méthodes de détection et Résultats Pregelatinized corn starch, Type A 9 g Detection methods and results
1. Pureté des échantillons  1. Purity of the samples
Conditions chromatographiques : colonne Cl 8 ; phase mobile : tampon phosphate 10mmol/L (ajusté à pH 7,0 avec NaOH) : acétonitrile 2 :7 (v/v) ; température de la colonne : 40°C ; longueur d'onde de détection : 220 nm ; méthode standard interne utilisée avec le composé de l'Exemple 1.  Chromatographic conditions: Cl 8 column; mobile phase: 10 mmol / L phosphate buffer (adjusted to pH 7.0 with NaOH): acetonitrile 2: 7 (v / v); column temperature: 40 ° C; detection wavelength: 220 nm; internal standard method used with the compound of Example 1.
Des solutions à 1 mg/ml des composés de l'invention sont préparées avec la phase mobile. 10 μΐ de chaque solution sont injectés dans le système de chromatographie liquide et les chromatogrammes sont enregistrés.  Solutions at 1 mg / ml of the compounds of the invention are prepared with the mobile phase. 10 μl of each solution are injected into the liquid chromatography system and the chromatograms are recorded.
Les composés de l'invention ont tous des puretés supérieures ou égales à 99%.  The compounds of the invention all have purities greater than or equal to 99%.
2. Stabilité 2. Stability
Des échantillons des composés des Exemples 1, 2 et 3 sont placés dans des incubateurs dans des conditions dénaturantes et la stabilité est déterminées par des mesures de DSC sur Samples of the compounds of Examples 1, 2 and 3 are placed in incubators under denaturing conditions and stability is determined by DSC measurements on
2 mois. Les résultats sont présentés dans le tableau 4 : 2 months. The results are shown in Table 4:
Tableau 4 Table 4
HR = Humidité" relative; BO = Bouteille Ouverte; BF = Bouteille Fermée RH = humidity "relative; BO = Open Bottle; BF = Closed Bottle
Les composes de l'invention sont stables dans des conditions fortement dénaturantes, ce qui est favorable à leur utilisation dans des compositions pharmaceutiques. The compounds of the invention are stable under strongly denaturing conditions, which is favorable for their use in pharmaceutical compositions.
3. Solubilité 3. Solubility
A l'aide d'une méthode standard externe, les composés des Exemples 1, 2 et 3 sont testés en HPLC, et comparés avec l'agomélatine de forme II. Les résultats sont présentés dans le tableau 5 sous forme de % d'accroissement de la solubilité par rapport à la solubilité de l'agomélatine de forme II : Tableau 5 Using an external standard method, the compounds of Examples 1, 2 and 3 are tested in HPLC, and compared with form II agomelatine. The results are shown in Table 5 as% increase in solubility versus solubility of Form II agomelatin: Table 5
Les résultats montrent que les complexes d' agomélatine et d'acides sulfoniques de la présente invention ont une solubilité supérieure à P agomélatine de forme II per se dans l'eau, dans HCI 0,1N, semblable aux fluides gastriques humains, ou dans un tampon à pH 6,8. Ces résultats montrent que les complexes ont un bien meilleur potentiel en terme de biodisponibilité que l'agomélatine de forme II.  The results show that the agomelatine and sulfonic acid complexes of the present invention have a higher solubility to form II agomelatine per se in water, in 0.1N HCl, similar to human gastric fluids, or in a buffer at pH 6.8. These results show that the complexes have a much better potential in terms of bioavailability than form II agomelatine.
4. Analyses DSC 4. DSC analyzes
Environ 5-10 mg des composés des Exemples 1, 2 et 3 sont pesés dans un creuset en aluminium fermé avec un couvercle en aluminium percé (non hermétique), sauf précision contraire. L'échantillon est introduit dans un appareil TA Q1000 (équipé avec un refroidi sseur), refroidi et maintenu à 25°C. Après stabilisation thermique, l'échantillon et la référence sont chauffés de 200°C à 250°C à une vitesse de 10°C/min et la réponse au flux thermique est enregistrée. L'azote est utilisé comme gaz de purge, à un débit de 100 cm /min.  About 5-10 mg of the compounds of Examples 1, 2 and 3 are weighed in a closed aluminum crucible with a drilled aluminum lid (non-hermetic) unless otherwise specified. The sample is introduced into a TA Q1000 (equipped with a cooler), cooled and maintained at 25 ° C. After thermal stabilization, the sample and reference are heated from 200 ° C to 250 ° C at a rate of 10 ° C / min and the response to heat flow is recorded. Nitrogen is used as a purge gas at a rate of 100 cm / min.
Les thermogrammes de DSC obtenus avec les composés des Exemples 1, 2 et 3 sont rapportés dans les Figures 2, 4 et 6.  The DSC thermograms obtained with the compounds of Examples 1, 2 and 3 are reported in Figures 2, 4 and 6.
5. Analyse de la structure cristalline 5. Crystal structure analysis
Les conditions de mesure des diagrammes de diffraction X sur poudre des produits des Exemples 1 , 2 et 3 sont les suivantes :  The conditions for measuring X-ray powder diffraction diagrams of the products of Examples 1, 2 and 3 are as follows:
Environ 50mg des composés des Exemples 1, 2 et 3 sont placés entre deux films Kapton® et fixé sur le support d'échantillons. L'échantillon est ensuite placé dans un diffractomètre PANALYTICAL XPERT-PRO MPD en mode transmission dans les conditions suivantes : Paramètres du générateur: 45 kV / 40 mA,  About 50 mg of the compounds of Examples 1, 2 and 3 are placed between two Kapton® films and fixed on the sample support. The sample is then placed in a PANALYTICAL XPERT-PRO MPD diffractometer in transmission mode under the following conditions: Generator parameters: 45 kV / 40 mA,
Configuration theta/theta  Theta / theta configuration
Anode : Cu -AlphaÎ [Â] 1,54060 Anode: Cu -Alpha [1,54060
K-Alpha2 [Â] 1 ,54443 K-Alpha2 [A] 1, 54443
K-Beta [A] 1,39225 K-Beta [A] 1.39225
K-A2 / K-Al Ratio 0,50000 K-A2 / K-Al Ratio 0.50000
Mode de balayage : continu de 3° à 55° (angle de Bragg 2 thêta)  Scan mode: continuous from 3 ° to 55 ° (Bragg 2 theta angle)
Pas [°2Th.] 0,0170  Not [° 2Th.] 0.0170
Durée du pas [s] 35,5301  Length of step [s] 35,5301
Angle de départ [°2ThJ 3,0034  Starting angle [° 2ThJ 3,0034
Angle de fin [°2Th.] 54,9894  End angle [° 2Th.] 54,9894
Rotation: oui  Rotation: yes
Les diagrammes de diffraction X sur poudre obtenus pour les Exemples 1, 2 et 3 sont représentés dans les Figures 1, 3 et 5. The X-ray powder diffraction patterns obtained for Examples 1, 2 and 3 are shown in Figures 1, 3 and 5.

Claims

REVENDICATIONS
L Complexes d'a omélatine et d'acides sulfoniques de formule (I) : Complexes of omelatine and of sulfonic acids of formula (I):
dans laquelle x représente 0 ou 1, et SO3H représente l'acide 1 ,5-naphtalène disulfonique ou l'acide benzène sulfonique .  wherein x is 0 or 1, and SO3H is 1, 5-naphthalene disulfonic acid or benzene sulfonic acid.
2. Complexe d'agomélatine de formule (I) selon la revendication 1 qui est le complexe agomélatine / acide 1,5-naphtalène disulfonique (2/1). 2. agomelatine complex of formula (I) according to claim 1 which is the complex agomelatine / 1,5-naphthalene disulfonic acid (2/1).
3. Complexe d'agomélatine de formule (I) selon la revendication 2 caractérisé par son diagramme de diffraction X sur poudre exprimé en termes de distance inter-réticulaire d, d'angle de Bragg 2 thêta (exprimés en °±0,2), et d'intensité relative suivant: 3. agomelatine complex of formula (I) according to claim 2 characterized by its powder X-ray diffraction diagram expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ± 0.2) , and of the following relative intensity:
2-Theta (°) exp. d (À) exp. intensity (%)  2-Theta (°) exp. d (To) exp. intensity (%)
6.3716 13.87229 18.97  6.3716 13.87229 18.97
1 1.3804 7.77552 17.98  1 1.3804 7.77552 17.98
11.9227 7.42299 36.06  11.9227 7.42299 36.06
12.5064 7.07784 100.00  12.5064 7.07784 100.00
12.6590 6.99288 13.75  12.6590 6.99288 13.75
14.5508 6.08767 44.17  14.5508 6.08767 44.17
15.5658 5.69292 1 1.96  15.5658 5.69292 1 1.96
16.2029 5.47051 42.63  16.2029 5.47051 42.63
16.9421 5.23346 25.85  16.9421 5.23346 25.85
17.6267 5.03171 18.67  17.6267 5.03171 18.67
19.4300 4.56857 49.04  19.4300 4.56857 49.04
20.2146 4.39301 22.77 20.2146 4.39301 22.77
21.4353 4.14550 17.80 21.4353 4.14550 17.80
21.6713 4.10090 22.84  21.6713 4.10090 22.84
22.2180 4.00121 64.19  22.2180 4.00121 64.19
22.4174 3.96607 10.83  22.4174 3.96607 10.83
24.0749 3.69664 29.61  24.0749 3.69664 29.61
24.5048 3.63275 13.33  24.5048 3.63275 13.33
25.1744 3.53763 20.58  25.1744 3.53763 20.58
25.7599 3.45853 23.59 incluant les formes dont les angles de diffraction correspondent à ±0.2° près.  25.7599 3.45853 23.59 including shapes with diffraction angles within ± 0.2 °.
4. Complexe d'agomélatine de formule (I) selon la revendication 1 qui est le complexe agomélatine / acide 1 ,5-naphthalène disulfonique (2/1) monohydrate. S. Complexe d'agomélatine de formule (I) selon la revendication 4 caractérisé par son diagramme de diffraction X sur poudre exprimé en termes de distance inter-réticulaire d, d'angle de Bragg 2 thêta (exprimés en °±0,2), et d'intensité relative suivant: 4. agomelatine complex of formula (I) according to claim 1 which is the complex agomelatine / acid 1, 5-naphthalene disulfonic acid (2/1) monohydrate. S. agomelatine complex of formula (I) according to claim 4 characterized by its powder X-ray diffraction pattern expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ± 0.2) , and of the following relative intensity:
2-Theta (°) exp. d (Â) exp. Intensity (%)  2-Theta (°) exp. d (Â) exp. Intensity (%)
9.6680 9.14852 12.45  9.6680 9.14852 12.45
12.4885 7.08796 57.23  12.4885 7.08796 57.23
12.6164 7.01639 28.61  12.6164 7.01639 28.61
14.5042 6.10715 57.42  14.5042 6.10715 57.42
16.2684 5.44863 25.67  16.2684 5.44863 25.67
16.4624 5.38484 32.93  16.4624 5.38484 32.93
16.8967 5.24739 90.90  16.8967 5.24739 90.90
19.3772 4.58091 10.50  19.3772 4.58091 10.50
22.4767 3.95573 100.00 22.4767 3.95573 100.00
23.4111 3.79992 20.49 23.4111 3.79992 20.49
23.5330 3.78051 44.02  23.5330 3.78051 44.02
23.6735 3.75840 21.92  23.6735 3.75840 21.92
24.0477 3.70076 13.67  24.0477 3.70076 13.67
24.5716 3.62303 13.43 24.5716 3.62303 13.43
25.1240 3.54460 12.46 25.1240 3.54460 12.46
26.6602 3.34374 19.10 26.6602 3.34374 19.10
28.1333 3.16930 12.0728.1333 3.16930 12.07
28.2443 3.15971 22.49 incluant les formes dont les angles de diffraction correspondent à ±0.2° près. 28.2443 3.15971 22.49 including shapes with diffraction angles within ± 0.2 °.
6. Complexe d'agomélatine de formule (I) selon la revendication 1 qui est le complexe agomélatine / acide benzène suffonique (2/1). 7. Complexe d'agomélatine de formule (I) selon la revendication 6 caractérisé par son diagramme de diffraction X sur poudre exprimé en termes de distance inter-réticulaire d, d'angle de Bragg 2 thêta (exprimés en °±0,2), et d'intensité relative suivant: 6. agomelatine complex of formula (I) according to claim 1 which is the complex agomelatine / benzene suffonic acid (2/1). 7. Agomelatine complex of formula (I) according to claim 6 characterized by its powder X-ray diffraction diagram expressed in terms of inter-reticular distance d, Bragg angle 2 theta (expressed in ± 0.2) , and of the following relative intensity:
2-Theta (°) exp. d (Â) exp. Intensity (%)  2-Theta (°) exp. d (Â) exp. Intensity (%)
8.0711 10.95469 35.25  8.0711 10.95469 35.25
12.6820 6.98026 68.37  12.6820 6.98026 68.37
12.7706 6.93203 65.37  12.7706 6.93203 65.37
13.0114 6.80427 15.18  13.0114 6.80427 15.18
13.3054 6.65458 31.84  13.3054 6.65458 31.84
14.9475 5.92700 19.42  14.9475 5.92700 19.42
15.1121 5.86283 70.19  15.1121 5.86283 70.19
15.4873 5.72160 14.16  15.4873 5.72160 14.16
16.1644 5.48344 12.98  16.1644 5.48344 12.98
17.2360 5.14486 21.06  17.2360 5.14486 21.06
18.1046 4.89993 36.33  18.1046 4.89993 36.33
18.6255 4.76406 10.91  18.6255 4.76406 10.91
18.8009 4.72001 33.43  18.8009 4.72001 33.43
20.0908 4.41978 30.26  20.0908 4.41978 30.26
20.4742 4.33788 42.37  20.4742 4.33788 42.37
20.6921 4.29270 56.78  20.6921 4.29270 56.78
20.8640 4.25771 26.42 20.8640 4.25771 26.42
21.7142 4.09289 13.88 21.7142 4.09289 13.88
23.3683 3.80679 15.16  23.3683 3.80679 15.16
23.6410 3.76349 100.00 23.6410 3.76349 100.00
24.9314 3.57154 26.81 24.9314 3.57154 26.81
25.6543 3.47253 10.71  25.6543 3.47253 10.71
27.5599 3.23660 14.00 incluant les formes dont les angles de diffraction correspondent à ±0.2° près.  27.5599 3.23660 14.00 including shapes with diffraction angles within ± 0.2 °.
8. Procédé d'obtention des complexes d'agomélatine et d'acides sulfoniques selon l'une des revendications 1 à 7 caractérisé en ce que : 8. Process for obtaining agomelatine and sulphonic acid complexes according to one of Claims 1 to 7, characterized in that:
l'agomélatine et les acides sulfoniques sont mélangés au sein d'un solvant organique ou hydro-organique aqueux dans les proportions désirées;  the agomelatine and the sulphonic acids are mixed in an aqueous organic or aqueous organic solvent in the desired proportions;
la solution obtenue est agitée et optionnellement chauffée à une température au plus égale à la température d'ébullition du solvant choisi ;  the solution obtained is stirred and optionally heated to a temperature at most equal to the boiling point of the chosen solvent;
le milieu est refroidi sous agitation et le co-cristal précipite naturellement ou précipite après reprise dans un deuxième solvant ;  the medium is cooled with stirring and the co-crystal precipitates naturally or precipitates after being taken up in a second solvent;
- le précipité obtenu est filtré et séché.  the precipitate obtained is filtered and dried.
9. Procédé de préparation des complexes d'agomélatine et d'acides sulfoniques selon l'une des revendications 1 à 7 caractérisé en ce que les deux constituants sont co-broyés. 9. Process for preparing the agomelatine and sulfonic acid complexes according to one of claims 1 to 7 characterized in that the two constituents are co-milled.
10. Procédé de préparation des complexes d'agomélatine et d'acides sulfoniques selon l'une des revendications 1 à 7 caractérisé en ce que les deux constituants sont mélangés au sein d'un solvant organique ou hydro-organique puis congelés et séchés à très basse température. 10. A process for preparing the agomelatine and sulfonic acid complexes according to one of claims 1 to 7 characterized in that the two constituents are mixed in an organic or hydro-organic solvent and then frozen and dried to a very high temperature. low temperature.
11. Procédé de préparation des complexes d'agomélatine et d'acides sulfoniques selon l'une des revendications 1 à 7 caractérisé en ce que les poudres d'agomélatine et de l'acide considéré sont mélangées dans un mélangeur, puis le mélange est extrudé par extrusion bi-vis sans filière pour obtenir un grain solide directement en sortie d'extrudeuse. 11. A process for the preparation of agomelatine and sulfonic acid complexes according to one of claims 1 to 7 characterized in that the powders of agomelatine and the acid in question are mixed in a mixer, and the mixture is extruded. by twin-screw extrusion without die to obtain a solid grain directly at the extruder outlet.
12. Compositions pharmaceutiques contenant comme principe actif un des complexes d'agomélatine et d'acides sulfoniques selon l'une des revendications 1 à 7, en combinaison avec un ou plusieurs véhicules inertes, non toxiques et pliarmaceutiquement acceptables. 12. Pharmaceutical compositions containing as active ingredient a complex of agomelatine and sulfonic acids according to one of claims 1 to 7, in combination with one or more inert vehicles, non-toxic and pliarcaceutically acceptable.
13. Compositions pharmaceutiques selon la revendication 12 utiles pour la fabrication de médicaments pour traiter les troubles du système mélatoninergique. 13. Pharmaceutical compositions according to claim 12 useful for the manufacture of medicaments for treating disorders of the melatoninergic system.
14. Compositions pharmaceutiques selon la revendication 12 utiles pour la fabrication de médicaments pour le traitement du stress, des troubles du sommeil, des troubles de l'anxiété et notamment du trouble anxiété généralisée, des troubles obsessionnels compulsifs, des troubles de l'humeur et notamment des troubles bipolaires, de la dépression majeure, des dépressions saisonnières, des pathologies cardiovasculaires, des pathologies du système digestif, des insomnies et fatigues dues aux décalages horaires, de la schizophrénie, des attaques de panique, de la mélancolie, des troubles de l'appétit, de l'obésité, de l'insomnie, de la douleur, des troubles psychotiques, de l'épilepsie, du diabète, de la maladie de Parkinson, de la démence sénile, des divers désordres liés au vieillissement normal ou pathologique, de la migraine, des pertes de mémoire, de la maladie d'Alzheimer, ainsi que dans les troubles de la circulation cérébrale ainsi que dans les dysfonctionnements sexuels, en tant qu'inhibiteurs de l'ovulation, d'immunomodulateurs et dans le traitement des cancers. 14. Pharmaceutical compositions according to claim 12 which are useful for the manufacture of medicaments for the treatment of stress, sleep disorders, anxiety disorders and in particular generalized anxiety disorder, obsessive-compulsive disorders, mood disorders and other disorders. bipolar disorder, major depression, seasonal depression, cardiovascular pathologies, digestive system pathologies, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy, appetite, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as in cerebral circulation disorders and dysfunction as ovulation inhibitors, immunomodulators and in the treatment of cancers.
15. Complexes d'agomélatine et d'acides sulfoniques de formule (I) selon l'une des revendications 1 à 7 pour le traitement des troubles du système mélatoninergique. 15. Complexes of agomelatine and sulfonic acids of formula (I) according to one of claims 1 to 7 for the treatment of disorders of the melatoninergic system.
16. Complexes d'agomélatine et d'acides sulfoniques de formule (I) selon l'une des revendications 1 à 7 pour le traitement du stress, des troubles du sommeil, des troubles de l'anxiété et notamment du trouble anxiété généralisée, des troubles obsessionnels compulsifs, des troubles de l'humeur et notamment des troubles bipolaires, de la dépression majeure, des dépressions saisonnières, des pathologies cardiovasculaires, des pathologies du système digestif, des insomnies et fatigues dues aux décalages horaires, de la schizophrénie, des attaques de panique, de la mélancolie, des troubles de l'appétit, de l'obésité, de l'insomnie, de la douleur, des troubles psychotiques, de l'épilepsie, du diabète, de la maladie de Parkinson, de la démence sénile, des divers désordres liés au vieillissement normal ou pathologique, de la migraine, des pertes de mémoire, de la maladie d'AIzheimer, ainsi que dans les troubles de la circulation cérébrale ainsi que dans les dysfonctionnements sexuels, en tant qu'inhibiteurs de l'ovulation, d'immunomodulateurs et dans le traitement des cancers. 16. Complexes of agomelatine and sulfonic acids of formula (I) according to one of claims 1 to 7 for the treatment of stress, sleep disorders, anxiety disorders including generalized anxiety disorder, obsessive-compulsive disorders, mood disorders including bipolar disorder, major depression, seasonal depression, cardiovascular diseases, digestive system pathologies, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as in cerebral circulation disorders and sexual dysfunction, as ovulation inhibitors, immunomodulators and in the treatment of cancers.
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